Gelnique

CLINICAL PHARMACOLOGY

Mechanism Of Action

Oxybutynin acts as a
competitive antagonist of acetylcholine at postganglionic muscarinic receptors,
resulting in relaxation of bladdersmooth muscle. Oxybutynin is a racemic
(50:50) mixture of R-and S-isomers. Antimuscarinic activity resides
predominantly with the R-isomer. The active metabolite, N-desethyloxybutynin,
has pharmacological activity on the human detrusor muscle that is similar to
that of oxybutynin in in vitro studies.

Pharmacokinetics

Absorption

Oxybutynin is transported
across intact skin and into the systemic circulation by passive diffusion
across the stratum corneum. Steady-state concentrations are achieved within 7
days of continuous dosing. Absorption of oxybutynin is similar when GELNIQUE is
applied to the abdomen, upper arm/shoulders or thighs. Mean plasma
concentrations during a randomized, crossover study of the three recommended
application sites in 39 healthy men and women are shown in Figure 1.

Distribution

Oxybutynin is widely
distributed in body tissues following systemic absorption. The volume of
distribution was estimated to be 193 L after intravenous administration of 5 mg
oxybutynin chloride.

Metabolism

Oxybutynin is metabolized primarily by the cytochrome
P450 enzyme systems, particularly CYP3A4, found mostly in the liver and gut
wall. Metabolites include phenylcyclohexylglycolic acid, which is
pharmacologically inactive, and Ndesethyloxybutynin (DEO), which is
pharmacologically active.

Transdermal administration of oxybutynin bypasses the
first-pass gastrointestinal and hepatic metabolism, reducing the formation of
the N-desethyloxybutynin metabolite. Only small amounts of CYP3A4 are found in
skin, limiting pre-systemic metabolism during transdermal absorption. The AUC
ratio of N-desethyloxybutynin metabolite to parent compound following multiple
transdermal applications is approximately 1:1 for GELNIQUE.

Following intravenous administration, the elimination
half-life of oxybutynin is approximately 2 hours. After the final steady-state
dose of GELNIQUE, oxybutynin and Ndesethyloxybutynin demonstrated biphasic
elimination with plasma concentrations beginning to decrease 24 hours after dosing.
Elimination was more rapid between 24 and 48 hours after dosing, during which
time plasma concentrations of oxybutynin and N-desethyloxybutynin declined by
about one-half. This rapid elimination phase was followed by a more prolonged
terminal elimination phase. The apparent elimination half-lives including the
terminal elimination phase were 64 hours and 82 hours for oxybutynin and DEO,
respectively.

Excretion

Oxybutynin is extensively metabolized by the liver, with
less than 0.1% of the administered dose excreted unchanged in the urine. Less
than 0.1% of the administered dose is excreted as the metabolite
N-desethyloxybutynin.

Person-to-Person Transference

The potential for dermal transfer of oxybutynin from a
treated person to an untreated person was evaluated in a single-dose study
where subjects dosed with GELNIQUE engaged in vigorous contact with an
untreated partner for 15 minutes, either with (N=14 couples) or without (N=12
couples) clothing covering the application area. The untreated partners not
protected by clothing demonstrated detectable plasma concentrations of
oxybutynin (mean Cmax = 0.94 ng/mL). Two of the 14 untreated subjects
participating in the clothing-to-skin contact regimen had measurable oxybutynin
plasma concentrations (Cmax < 0.1 ng/mL) during the 48 hours following
contact with treated subjects; oxybutynin was not detectable with the remaining
12 untreated subjects.

Use of Sunscreen

The effect of sunscreen on the absorption of oxybutynin
when applied 30 minutes before or 30 minutes after GELNIQUE application was
evaluated in a single-dose randomized crossover study (N=16). Concomitant
application of sunscreen, either before or after GELNIQUE application, had no
effect on the systemic exposure of oxybutynin.

Showering

The effect of showering on the absorption of oxybutynin
was evaluated in a randomized, steady-state crossover study under conditions of
no shower, or showering 1, 2 or 6 hours after GELNIQUE application (N=20). The
results of the study indicate that showering after one hour does not affect the
overall systemic exposure to oxybutynin.

Race

The effect of race on the pharmacokinetics of GELNIQUE
has not been studied.

Specific Populations

Geriatric: Available data suggest that there are
no significant differences in the pharmacokinetics of oxybutynin based on geriatric
status in patients following administration of GELNIQUE [see Use in Specific
Populations].

Pediatric: The pharmacokinetics of oxybutynin and
N-desethyloxybutynin have not been evaluated in individuals younger than 18
years of age [seeUse in Specific Populations].

Gender: Available data suggest that there are no
significant differences in the pharmacokinetics of oxybutynin based on gender
in healthy volunteers following administration of GELNIQUE.

Renal Impairment: The effect of renal impairment
on the pharmacokinetics of GELNIQUE has not been studied.

Hepatic Impairment: The effect of hepatic
impairment on the pharmacokinetics of GELNIQUE has not been studied.

Clinical Studies

The efficacy and safety of GELNIQUE were evaluated in a
single randomized, double-blind, placebo-controlled, parallel group 12-week
study for the treatment of overactive bladder with symptoms of urge
incontinence, urgency and frequency. Key entry criteria included adults with
symptomatic overactive bladder with an average of ≥ 4 incontinence
episodes in a 3-day period and at least 8 micturitions per day. Patients were
randomized to daily applications of GELNIQUE 1 gram or matching placebo gel. A
total of 389 patients received GELNIQUE and 400 patients received placebo gel.
The majority of patients were Caucasian (86.3%) and female (89.2%), with a mean
age of 59.4 years (range: 18 to 88 years). The average duration of urinary
incontinence was approximately 8.5 years and approximately 75% of patients had
no prior pharmacological treatment for urinary incontinence.

Patients treated with GELNIQUE experienced a
statistically significant decrease in the number of urinary incontinence
episodes per day from baseline to endpoint compared with placebo (p < 0.0001)
as well as a decrease in the average daily urinary frequency (p=0.0017) and an
increase in the average urine volume per void (p=0.0018).